JPWO2020049786A1 - Combination medications, preventive or inhibitory agents of pyrimidine antimetabolite resistance, and treatment of the disease - Google Patents

Abstract

The subject of the present invention is a combination drug capable of preventing or suppressing the acquisition of resistance to a pyrimidine antimetabolite, a preventive or inhibitory agent for preventing or suppressing the resistance of a pyrimidine antimetabolite, and a method for treating a disease using the above combination drug. To provide. According to the present invention, it is a combination drug containing a pyrimidine antimetabolite and 5-hydroxy-1H-imidazol-4-carboxamide, and the single dose of Compound A is 50 to 500 mg / m2, and the drug is administered daily. Combination formulations are provided in amounts of 100-1000 mg / m2.

Description

The present invention relates to a combination drug comprising a pyrimidine antimetabolite and 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof. The present invention further relates to a prophylactic or inhibitor of resistance to pyrimidine antimetabolites. The present invention further relates to a method for treating a disease using the above-mentioned combination drug.

5-Hydroxy-1H-imidazol-4-carboxamide (hereinafter, also referred to as compound A) or a salt thereof or a hydrate thereof is a compound medically useful as an anticancer agent because it has a strong anticancer effect. Yes (Patent Documents 1 to 8). Compound A is being investigated for application to diseases such as myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and acute myelogenous leukemia (AML) (Non-Patent Documents 1 and 2).

On the other hand, pyrimidine antimetabolites such as azacitidine are used in the treatment of cancer because they inhibit the functions of RNA and DNA, thereby inhibiting the growth and division of tumor cells and normalizing the abnormal function of genes. ing.

Compound A has been reported to exhibit cell proliferation inhibitory activity without exhibiting cross resistance to azacitidine-resistant leukemia cell lines (Non-Patent Document 3). Further, it is described that the AML cell line is treated with a combination of Compound A and azacitidine (Non-Patent Document 4).

Japanese Unexamined Patent Publication No. 53-32124 International Publication No. 2009/035168 Pamphlet International Publication No. 2013/047758 Pamphlet International Publication No. 2014/112529 Pamphlet International Publication No. 2014/112530 Pamphlet International Publication No. 2014/112531 Pamphlet International Publication No. 2015/105174 Pamphlet International Publication No. 2018/051971 Pamphlet

Cancer and Chemotherapy, Vol. 16, No. 1, 123-130, 1989 Cancer research Vol. 42, pp. 1098-1102, 1982 Pharma Res Per, 4 (1), 2016, e00206 Leukemia Research 59 (2017) 85-92

When pyrimidine antimetabolites such as azacitidine are used for the treatment of cancer, cases of recurrence due to resistance acquisition become a problem. It is desired to suppress or prevent the acquisition of resistance of pyrimidine antimetabolites. Non-Patent Document 3 describes that compound A does not exhibit cross resistance to azacitidine-resistant leukemia cell lines, but it is unclear whether compound A suppresses the acquisition of azacitidine resistance. Also in Non-Patent Document 4, it is unclear whether or not compound A can suppress the acquisition of azacitidine resistance in cells before acquiring azacitidine resistance.

The present invention provides a combination drug containing a pyrimidine antimetabolite and 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof, which can prevent or suppress the acquisition of resistance to the pyrimidine antimetabolite. Providing is an issue to be solved. The present invention further aims to provide a prophylactic or inhibitory agent for resistance to pyrimidine antimetabolites. Further, the present invention is a problem to be solved to provide a method for treating a disease using the above-mentioned combination drug.

As a result of intensive studies to solve the above problems, the present inventors have administered a pyrimidine antimetabolite and 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof in a predetermined manner. We have found that the above-mentioned problems can be solved by administering the drug in an amount and at a predetermined timing, and have completed the present invention.

The present invention provides:
(1) Pyrimidine antimetabolite and
A combination drug comprising 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof.
A single dose of 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is 50 to 500 mg / m ² , and a daily dose is 100 to 1000 mg / m ² . Combination drug.
(2) The combination drug according to (1), wherein resistance to a pyrimidine antimetabolite is prevented or suppressed.
(3) The combination drug according to (1) or (2), wherein the administered patient exhibits at least one improvement as follows.
(A) The median time to AML transition or death is 14.0 months or greater.
(B) The median time to AML transition is 21.0 months or longer.
(C) The proportion of patients who became independent from red blood cell transfusion dependence is 48% or more.
(D) The proportion of patients who became independent from platelet transfusion dependence is 45% or more.
(4) The combination drug according to (2), wherein the period during which resistance to the pyrimidine antimetabolite can be prevented or suppressed is 3 months or longer.
(5) The combination drug according to any one of (1) to (4), wherein the pyrimidine antimetabolite is a compound selected from the group of azacitidine, decitabine, cytarabine and gemcitabine or a salt thereof or a hydrate thereof.
(6) To any one of (1) to (5), the single dose of 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is 370 to 430 mg / m ^2. The combination drug described.

(7) The pyrimidine antimetabolite is azacitidine or a salt thereof or a hydrate thereof, and the daily dose of azacitidine or a salt thereof or a hydrate thereof is 70 to 80 mg / m ² , (1) to (6). ) The combination drug according to any one of.
(8) The method according to any one of (1) to (7), wherein the pyrimidine antimetabolite is azacitidine or a salt thereof or a hydrate thereof, and azacitidine or a salt thereof or a hydrate thereof is administered for 7 days or more. Combination medicine.
(9) The pyrimidine antimetabolite is azacitidine or a salt thereof or a hydrate thereof, and azacitidine or a salt thereof or a hydrate thereof is administered multiple times with a 7-day administration period and a subsequent drug holiday as one cycle. The combination drug according to any one of (1) to (8), which is administered in the cycle of (1) to (8).
(10) The combination drug according to any one of (1) to (9), wherein 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is administered for 14 to 28 days.
(11) Any of (1) to (10), in which 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is administered one day or more before or on the same day as the administration of the pyrimidine antimetabolite. The combination drug described in 1.
(12) Pyrimidine antimetabolite is intravenously administered by intravenous drip, and 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is intravenously orally administered by intravenous drip, from (1) to (1). The combination drug according to any one of 11).

(13) The combination drug according to any one of (1) to (12) for the treatment of blood cancer.
(14) The combination drug according to any one of (1) to (13) for the treatment of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
(15) A pyrimidine antimetabolite and 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof are provided as the same or separate pharmaceutical compositions, (1) to (14). ) The combination drug according to any one of.
(16) A prophylactic or inhibitory agent for resistance to a pyrimidine antimetabolite, which comprises 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof.
(17) A method for treating a disease, which comprises administering azacitidine or a salt thereof or a hydrate thereof and 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof. Alternatively, the daily dose of the salt or its hydrate is 70 to 80 mg / m ² , and the single dose of 5-hydroxy-1H-imidazol-4-carboxamide or its salt or its hydrate is 50 to 50 to. was 500 mg / ^{m 2,} the method daily dosage is 100-1000 mg / ^{m 2.}

(A) The single dose of 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is 50 to 500 mg / m ² , and the daily dose is 100 to 1000 mg / m ² . , Pyrimidine metabolite antagonist and 5-hydroxy-1H-imidazole-4-carboxamide or a salt thereof or a hydrate thereof simultaneously, or 5-hydroxy-1H-imidazole- prior to administration of pyrimidin metabolite antagonist. Use of pyrimidine metabolism antagonist and 5-hydroxy-1H-imidazole-4-carboxamide or salt thereof or hydrate thereof for the production of a combination drug for administering 4-carboxamide or a salt thereof or a hydrate thereof. ..

(B) The single dose of 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is 50 to 500 mg / m ² , and the daily dose is 100 to 1000 mg / m ² . , Pyrimidine metabolism antagonist and 5-hydroxy-1H-imidazole-4-carboxamide or a salt thereof or a hydrate thereof are administered simultaneously, or 5-hydroxy-1H-imidazole- prior to administration of the pyrimidine metabolism antagonist. A pyrimidine metabolism antagonist and a 5-hydroxy-1H-imidazole-4-carboxamide or a salt thereof or a hydrate thereof for use in a treatment in which 4-carboxamide or a salt thereof or a hydrate thereof is administered.

According to the present invention, resistance to pyrimidine antimetabolites can be prevented or suppressed.

FIG. 1 shows the results of cell proliferation tests for the acquisition of azacitidine resistance of leukemia cell lines and the preventive or inhibitory effect of compound A.

The present invention will be described in detail below.
% As used in the present invention means mass percentage unless otherwise specified. The numerical range indicated by using "~" in the present invention indicates a range including the numerical values before and after "~" as the minimum value and the maximum value, respectively. Further, in the present invention, the amount of each component in the composition means the total amount of the plurality of substances present in the composition when a plurality of substances corresponding to each component are present in the composition, unless otherwise specified. do.
As used in the present invention, "mg / m ² " means the dose per body surface area.

Prevention means inhibition of onset, reduction of onset risk or delay of onset.
Treatment means improvement or suppression of progression of the disease or condition of interest.
Treatment means prevention or treatment of various diseases.

The present invention is a combination drug comprising a pyrimidine metabolism antagonist and 5-hydroxy-1H-imidazol-4-carboxamide (Compound A) or a salt thereof or a hydrate thereof, wherein the compound A or a salt thereof or a salt thereof is used. A single dose of hydrate is 50-500 mg / m ² and a daily dose is 100-1000 mg / m ² , with the pyrimidine metabolite antagonist and compound A or a salt thereof or a hydrate thereof. The present invention relates to a combination drug, which is administered at the same time or is administered with Compound A or a salt thereof or a hydrate thereof prior to administration of a pyrimidine metabolism antagonist.

In the combination drug of the present invention, the pyrimidine antimetabolite and compound A or a salt thereof or a hydrate thereof may be provided as the same pharmaceutical composition or may be provided as separate pharmaceutical compositions. good. Provided as the same pharmaceutical composition means that the pyrimidine antimetabolite and compound A or a salt thereof or a hydrate thereof are provided in a form contained in one pharmaceutical composition.

According to the combination drug of the present invention, resistance to the pyrimidine antimetabolite can be prevented or suppressed. The presumed mechanism for preventing or suppressing the resistance of a pyrimidine antimetabolite by Compound A or a salt thereof or a hydrate thereof will be described below. Aza represents azacitidine.

The intracellular CTP (cytidine triphosphate) competes with Aza-CTP (the active metabolite of Aza), and increased CTP may reduce Aza sensitivity. It has been demonstrated that the amount of CTP in Aza-resistant leukemia cells was 5-fold higher than that in Aza-sensitive cells, and compound A or a salt thereof or a hydrate thereof has an inhibitory effect on CTP (an effect of suppressing increase in CTP). Has. Increased amounts of CTP were observed in response to the acquisition of Aza resistance after exposure of leukemia cells to Aza for 4 months. Therefore, long-term exposure of Compound A or a salt thereof or a hydrate thereof and Aza is beneficial in restoring Aza sensitivity in anticipation of an inhibitory effect on CTP of Compound A or a salt thereof or a hydrate thereof. This study was conducted on the assumption that there is.

As a result, when leukemia cells were exposed for a long period of time (4 months) with a combination of Aza and 3/4 hydrate of Compound A, Aza sensitivity changed. Exposure of naive leukemia cells (SKM-1) to Aza and compound A (1 μmol / L or 10 μmol / L) for 4 months was able to almost completely eliminate the acquisition of Aza resistance. In addition, Aza alone caused an increase in the amount of intracellular CTP in the treatment for 4 months and acquired resistance. Combining Aza and Compound A from the start of treatment revealed that the intracellular CTP level was maintained at the level of untreated cells. These results indicate that compound A or a salt thereof or a hydrate thereof suppresses resistance acquisition by preventing the intracellular CTP amount from increasing in the process of acquiring Aza resistance. Therefore, treating untreated MDS patients with a combination of Aza and Compound A or a salt thereof or a hydrate thereof is considered to be effective in maintaining Aza sensitivity.

[1] Pyrimidine antimetabolite A pyrimidine base is a component of DNA required for cell proliferation. A pyrimidine antimetabolite has a structure similar to that of a pyrimidine base, and can exhibit a cell proliferation inhibitory effect by being incorporated into a DNA strand instead of a pyrimidine base in a DNA synthesis process.

It is known that all pyrimidine antimetabolites exert their medicinal effects by being converted into triphosphates, which are active substances in cells, and competing with CTP. Therefore, it is expected that pyrimidine antimetabolites other than azacitidine are also likely to be mediated by an increase in intracellular CTP level as one of the resistance-imparting mechanisms, as in the case of azacitidine. Therefore, it is considered that compound A or a salt thereof or a hydrate thereof can suppress the resistance of pyrimidine antimetabolites other than azacitidine by the same mechanism of action as in the case of azacitidine.

Examples of the pyrimidine antimetabolite include, but are not limited to, the following compounds or salts thereof or hydrates thereof.
Azacitidine (also called 5-azacitidine) (4-amino-1-β-D-ribofuranosyl-1,3,5-triazine-2 (1H) -on)
-Decitabine (5-aza-2'-deoxycytidine)
・ Cytarabine (Arabinosyl cytosine)
Gemcitabine (2'-deoxy-2', 2'-difluorocytidine)
Zebularine (2 (1H) -pyrimidine-riboside)
Emtricitabine (2', 3'-dideoxy-5-fluoro-3'-thiacitidine)
-Capecitabine (N ⁴ -pentyloxycarbonyl-5'-deoxy-5-fluorocytidine)
・ 2'-Cyclocytidine,
- arabinofuranosyl (arabinofuanosyl) -5- ^{azacytidine-dihydro-5-azacytidine-N 4} - octadecyl - cytarabine elaidic acid cytarabine, and - cytosine 1-beta-D-arabinofuranoside

As the pyrimidine antimetabolite, preferably, a compound selected from the group of azacitidine, decitabine, cytarabine and gemcitabine or a salt thereof or a hydrate thereof can be used, and particularly preferably azacitidine or a salt thereof or a hydrate thereof. Can be used.

As the pyrimidine antimetabolite, one kind of compound may be used, or two or more kinds of compounds may be used.

Salts in pyrimidine antimetabolites include commonly known salts in basic or acidic groups.
Examples of the salt of the basic group include salts with mineral acids such as hydrochloric acid, hydrogen bromide, phosphoric acid and sulfuric acid; tartrate acid, formic acid, acetic acid, fumaric acid, maleic acid, citric acid, trichloroacetic acid and trifluoroacetic acid and the like. Examples thereof include salts with organic carboxylic acids and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

Examples of salts of acidic groups include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts and trimethylamine, triethylamine, tributylamine, tromethamole, pyridine, N, N. -Dimethylaniline, N-methylpiperidin, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine and salts with nitrogen-containing organic bases such as N, N'-dibenzylethylenediamine. And so on.
Furthermore, among the above salts, preferred salts include pharmacologically acceptable salts.

When the pyrimidine antimetabolite is azacitidine or a salt thereof or a hydrate thereof, the daily dose of azacitidine or a salt thereof or a hydrate thereof is preferably 20 to 200 mg / m 2 and more preferably 50 to 50 to ^{m 2.} It was 100 mg / ^{m 2,} more preferably from 60~90mg / ^{m 2,} more preferably from 70~80mg / ^{m 2,} particularly preferably 75 mg / ^{m 2.}

When the pyrimidine antimetabolite is azacitidine or a salt thereof or a hydrate thereof, azacitidine or a salt thereof or a hydrate thereof is preferably administered for 7 days.
When the pyrimidine antimetabolite is azacitidine or a salt thereof or a hydrate thereof, the pyrimidine or a salt thereof or a hydrate thereof is used in multiple cycles with a 7-day administration period and a subsequent drug holiday as one cycle. It is preferable to administer with. The drug holiday may be 7 to 28 days, 14 to 28 days, or 18 to 24 days.

The multiple cycles are preferably at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, or at least 15 times. Is.

If pyrimidine antimetabolite is cytarabine or a salt thereof or a hydrate thereof, a daily dosage of cytarabine or a salt thereof or a hydrate thereof is preferably ^{1g / m 2 ~10g / m 2} , more preferably is ^{2g / m 2 ~6g / m 2} , more preferably from ^{3g / m 2 ~5g / m 2} .

When the pyrimidine antimetabolite is cytarabine or a salt thereof or a hydrate thereof, cytarabine or a salt thereof or a hydrate thereof is preferably administered for 5 days or more, and preferably for 6 days or more.
When the pyrimidine antimetabolite is cytarabine or a salt thereof or a hydrate thereof, cytarabine or a salt thereof or a hydrate thereof is administered multiple times with a administration period of 5 to 6 days followed by a drug holiday. It is preferable to administer in the cycle of. The drug holiday may be 7 to 28 days, 14 to 28 days, or 18 to 24 days.

The multiple cycles are preferably at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, or at least 15 times. Is.

As an example of administration when the pyrimidine antimetabolite is cytarabine or a salt thereof or a hydrate thereof, 2 g / m ² is mixed with 5% glucose solution or physiological saline solution to make 300 to 500 mL at a time for 12 hours. It can be administered intravenously daily for up to 6 days by infusion over 3 hours each time.

When the pyrimidine antimetabolite is decitabine or a salt thereof or a hydrate thereof, the daily dose of decitabine or a salt thereof or a hydrate thereof is preferably 4 to 100 mg / m ² , more preferably 8 to 8 to. was 50 mg / ^{m 2,} more preferably from 10 to 30 mg / ^{m 2,} particularly preferably 15 to 25 mg / ^{m 2.}

When the pyrimidine antimetabolite is decitabine or a salt thereof or a hydrate thereof, it is preferable to administer decitabine or a salt thereof or a hydrate thereof for 4 days or more or 5 days or more.
When the pyrimidine antimetabolite is decitabine or a salt thereof or a hydrate thereof, a plurality of decitabine or a salt thereof or a hydrate thereof have a administration period of 4 to 6 days and a subsequent drug holiday as one cycle. It is preferably administered in multiple cycles. The drug holiday may be 7 to 28 days, 14 to 28 days, or 22 to 24 days.

The multiple cycles are preferably at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, or at least 15 times. Is.

As an example of administration when the pyrimidine antimetabolite is decitabine or a salt thereof or a hydrate thereof, 20 mg / m ² of decitabine is continuously infused once a day for 1 hour or more every day for 5 days. One cycle is to take the drug off for 23 days, and the drug is administered in a plurality of cycles.

The method for administering the pyrimidine metabolite antagonist may be either oral administration or parenteral administration (for example, subcutaneous administration, injection, infusion, administration to the rectal site, etc.), but parenteral administration is preferable, and more preferably. Subcutaneous administration or intravenous administration, particularly preferably intravenous administration by infusion.

When the pyrimidine antimetabolite is administered parenterally, the pyrimidine antimetabolite can be provided as a pharmaceutical composition in the form of a solution or suspension. Pharmaceutical compositions for parenteral administration include aqueous media, water-miscible media, non-aqueous media, antibacterial agents, preservatives, stabilizers, solubility improvers, isotonic agents, buffers, antioxidants, topical agents. It may contain an anesthetic, a suspension and dispersant, a wetting or emulsifying agent, a complexing agent, a metal ion sequestering agent and a chelating agent, a cryoprotectant, a lysis protective agent, a pH adjusting agent and the like.

Aqueous media include water, saline, saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer injection, isotonic dextrose injection, sterile water injection, dextrose and Ringer lactate injection. Included, but not limited to. Non-aqueous media include plant-derived fixed oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, benivana oil, sesame oil, soybean oil, hardened vegetable oil, hardened soybean oil, and medium-chain triglyceride of palm oil. And includes, but is not limited to, palm seed oils. Water-miscible media include ethanol, 1,3-butanediol, liquid polyethylene glycol (eg polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N, N-dimethylacetamide. , And dimethyl sulfoxide, but not limited to these.

Antibacterial agents or preservatives include phenol, cresol, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, timerosal, benzalkonium chloride (eg, benzethonium chloride), methyl- and propylparaben, and sorbic acid. However, it is not limited to these. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin and dextrose.

Buffers include, but are not limited to, phosphates and citrates.
Antioxidants include sulfites and sodium metabisulfite.
Local anesthetics include, but are not limited to, procaine hydrochloride.
Suspensions and dispersants include sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone and the like.
Emulsifiers include polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, triethanolamine oleate and the like.
Sequestrants or chelators include, but are not limited to, EDTA.
pH regulators include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
Complexing agents include cyclodextrins such as α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin. , Not limited to these.

[2] 5-Hydroxy-1H-imidazol-4-carboxamide (Compound A)
In the present invention, the single dose of compound A or a salt thereof or a hydrate thereof is 50 to 500 mg / m ² , preferably 370 to 430 mg / m ² , and more preferably 390 to 410 mg / m ² . be. From the viewpoint of preventing or suppressing the resistance of the pyrimidine antimetabolite while reducing side effects, the single dose is preferably 100 to 350 mg / m ² , preferably 180 to 320 mg / m. ^{It is 2} , preferably 200 to 300 mg / m ² . The preferred single dose in this case is 200 mg / m ² or 300 mg / m ² .

The daily dose is 100 to 1000 mg / m ² , and the number of administrations is preferably divided into two or more times a day. The daily dose is preferably 740-860 mg / m ² , more preferably 780-820 mg / m ² . ^{The daily dose is preferably 200 to 750 mg / m 2} , preferably 360 to 840 mg / m 2, from the viewpoint of obtaining a sufficient effect of preventing or suppressing the resistance of the pyrimidine antimetabolite while reducing side effects. It is m ² , preferably 400 to 600 mg / m ² .

The method of administration of compound A or a salt thereof or a hydrate thereof may be either oral administration or parenteral administration (for example, subcutaneous, injection, infusion and administration to the rectal site), but subcutaneous or oral administration is preferable. Yes, more preferably oral administration.

The administration period of compound A or a salt thereof or a hydrate thereof is, for example, 28 days as one cycle, preferably 14 days to 28 days, and more preferably 14 days to 21 days in one cycle.

In the present invention, the pyrimidine antimetabolite and compound A or a salt thereof or a hydrate thereof are administered at the same time, or compound A or a salt thereof or a hydrate thereof is administered prior to the administration of the pyrimidine antimetabolite. .. Preferably, compound A or a salt thereof or a hydrate thereof is administered at least 1 day before administration of the pyrimidine antimetabolite.

Examples of the salt of compound A include salts in commonly known basic groups or acidic groups.
Examples of the salt of the basic group include salts with mineral acids such as hydrochloric acid, hydrogen bromide, phosphoric acid and sulfuric acid; tartrate acid, formic acid, acetic acid, fumaric acid, maleic acid, citric acid, trichloroacetic acid and trifluoroacetic acid and the like. Examples thereof include salts with organic carboxylic acids and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

Examples of salts of acidic groups include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts and trimethylamine, triethylamine, tributylamine, tromethamole, pyridine, N, N. -Dimethylaniline, N-methylpiperidin, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine and salts with nitrogen-containing organic bases such as N, N'-dibenzylethylenediamine. And so on.
Further, among the above-mentioned salts, a preferred salt of Compound A includes a pharmacologically acceptable salt.

As the hydrate of Compound A or a salt thereof, the hydrate of Compound A produced by the method described in JP-A-58-24569, produced by the method described in WO 2009/035168. Examples thereof include hydrates of compound A, hydrates of compound A produced by the method described in Japanese Patent Application No. 2017-208570, hydrates of compound A synthesized by the method described in Examples described later, and the like. ..

With respect to Compound A, the term "Compound A or a salt thereof or a hydrate thereof" refers to Compound A, a salt of Compound A, a hydrate of Compound A, and a hydrate of a salt of Compound A, unless otherwise specified. When "comprising compound A or a salt thereof or a hydrate thereof" is used, unless otherwise specified, compound A, a salt of compound A, a hydrate of compound A, etc. And at least one selected from the group consisting of hydrates of the salt of compound A.

Compound A or a salt thereof or a hydrate thereof used in the present invention can be produced, for example, by the method described in Production Example 1 described later.

When compound A or a salt thereof or a hydrate thereof is used in the combination drug of the present invention, compound A or a salt thereof or a hydrate thereof can be provided as a pharmaceutical composition together with an additive.
Tablets are preferred as the form of the pharmaceutical composition containing compound A. The content of compound A or a salt thereof or a hydrate thereof can be 0.3 to 95% of the tablet mass, preferably 20 to 90%, more preferably 40 to 85%.

For example, the form, manufacturing method, additives, description, etc. ([0015] to [0041]) of the tablets described in International Publication No. 2014/112530 (US Patent Application Publication No. 2015/0057324) are incorporated and taken into consideration. These contents can be incorporated in the specification of the present application.
Preferred tablets contain Compound A. 3/4 hydrate, silicon dioxide and crystalline cellulose. By adding crystalline cellulose, it is possible to prevent capping in which the tablet peels into a cap shape.

When crystalline cellulose is added, the content of crystalline cellulose is preferably 0.1 to 20% by mass, more preferably 1 to 15% by mass, further preferably 2 to 12% by mass, and 3 to 10% by mass of the tablet mass. Is the most preferable.
When crystalline cellulose is added, the content of Compound A. 3/4 hydrate is preferably 60 to 80% by mass, more preferably 65 to 75% by mass, based on the tablet mass.
The above tablets may further contain other additives described in WO2014 / 112530, and suitable types and amounts of the additives refer to the description of WO2014 / 112530. You can take it into consideration.

[3] Prophylactic or inhibitory agent for resistance to pyrimidine antimetabolite According to the present invention, pyrimidine metabolism containing 5-hydroxy-1H-imidazol-4-carboxamide (Compound A) or a salt thereof or a hydrate thereof. Antiseptic or inhibitory agents for the resistance of antagonists are provided. Details of the form of the preventive or inhibitory agent for the resistance of the pyrimidine antimetabolite are as described in [2] above. When used as a prophylactic or inhibitory agent, it may be administered at the same time as the pyrimidine antimetabolite or prior to the administration of the pyrimidine antimetabolite. When used as a prophylactic or inhibitor, the daily dose may be similar to that used in combination with the pyrimidine antimetabolites described above. The single dose is 50 to 500 mg / ^{m 2,} often even 50~420mg / ^{m 2,} often even 50~320mg / ^{m 2,} may be 50~220mg / ^{m 2.} It is preferable to administer the above-mentioned single dose twice a day, and the daily dose is twice the above-mentioned single dose.
The preferred single dose is 200 mg / m ² or 300 mg / m ² , in which case the effect of preventing or suppressing the resistance to the pyrimidine antimetabolite can be sufficiently obtained while reducing side effects.

[4] Uses The use of the combination drug of the present invention is not particularly limited, but can be preferably used for the treatment of blood cancer, and more preferably myelodysplastic syndrome (MDS) or acute myeloid leukemia. It can be used for the treatment of leukemia (AML), especially preferably for MDS.

Hematological cancers include, but are not limited to, leukemia, MDS, malignant lymphoma, and multiple myeloma.

In the present invention, "leukemia" means a symptomatology of leukemia and a symptomatology associated with leukemia.
In the present invention, "leukemia" is a general term for diseases in which tumorigenic hematopoietic cells proliferate indefinitely and appear in blood. In leukemia, those in which tumor cells have lost their differentiation potential are called acute leukemia, and those in which tumor cells retain their differentiation potential are called chronic leukemia. Further, when the cell from which the tumor originated is a myeloid cell, it is classified as myeloid leukemia, or when it is a lymphocytic cell, it is classified as lymphocytic leukemia. From this, the leukemias are broadly acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML). It is classified into four types of leukemia (CLL), including acute premyelogenous leukemia (APL), atypical leukemia (AUL), myelogenous leukemia (AMMOL), and juvenile chronic myelogenous leukemia (JCML). Included in the classification of. In addition, acute monocytic leukemia (AMOL), chronic monocytic leukemia (CMOL), red leukemia, eosinophil leukemia, basal leukemia, macronuclear blast leukemia, plasmacytotic leukemia, green tumor, chronic Leukemia types include neutrophil leukemia, adult T-cell leukemia, lymphosarcoma cell leukemia, hairy cell leukemia, and pre-lymphocytic leukemia.

Myelodysplastic Syndrome (MDS) is a heterogeneous group grouped together due to the presence of one or more hematopoietic dysplastic changes, including dysplastic changes in the myeloid, erythroid, and megakaryocyte systems. It is a cloned hematopoietic stem cell disorder. These changes result in cytopenia in one or more of the three strains. Patients with MDS typically develop complications associated with anemia, neutropenia (infection), or thrombocytopenia (bleeding). Generally, about 10% to 70% of MDS patients develop acute leukemia.

[5] Treatment method and use of diseases According to the present invention, azacitidine or a salt thereof or a hydrate thereof and 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof are administered. A method for treating a disease including, wherein the daily dose of azacitidine or a salt thereof or a hydrate thereof is 70 to 80 mg / m ² , and 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a salt thereof or The single dose of the hydrate is 50-500 mg / m ² and the daily dose is 100-1000 mg / m ² , with azacitidine or a salt thereof or a hydrate thereof and 5-hydroxy-1H. -Imidazole-4-carboxamide or a salt thereof or a hydrate thereof is administered simultaneously, or 5-hydroxy-1H-imidazole-4-carboxamide or a salt thereof or a salt thereof or a salt thereof prior to administration of azacitidine or a salt thereof or a hydrate thereof. A method of administering the hydrate is provided. Suitable single dose and daily dose are the same as in [2] above.

According to the present invention, further, the single dose of 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is 50 to 500 mg / m 2, and the daily dose is 100 to 1000 ^{mg / m 2.} m ^2, and pyrimidine antimetabolites, 5-hydroxy -1H- imidazole-4-carboxamide or a salt thereof or administering a hydrate thereof and at the same time, prior to the administration of the pyrimidine antimetabolites 5-hydroxy - A pyrimidine metabolism antagonist and a 5-hydroxy-1H-imidazole-4-carboxamide or a salt thereof or water thereof for the production of a combination drug to which 1H-imidazole-4-carboxamide or a salt thereof or a hydrate thereof is administered. The use of Japanese products is offered.

According to the present invention, further, the single dose of 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is 50 to 500 mg / m 2, and the daily dose is 100 to 1000 ^{mg / m 2.} m ^2, and pyrimidine antimetabolites, 5-hydroxy -1H- imidazole-4-carboxamide or a salt thereof or administering a hydrate thereof and at the same time, prior to the administration of the pyrimidine antimetabolites 5-hydroxy - A pyrimidine metabolism antagonist and a 5-hydroxy-1H-imidazole-4-carboxamide or a salt thereof or a hydrate thereof for use in a treatment in which 1H-imidazole-4-carboxamide or a salt thereof or a hydrate thereof is administered. Is provided.

The present invention will be described with reference to the following examples, but the present invention is not limited thereto.

The present invention will be described with reference to reference examples, synthetic examples, examples, and the like, but the present invention is not limited thereto. Unless otherwise specified, "%" means "mass%".
The infrared absorption spectrum (hereinafter referred to as IR) was measured by the ATR method (Attenuated Total Reflection method).
The water content was measured by the Karl Fischer method.
The seed crystals used in Examples and Comparative Examples were produced in the same manner as described in International Publication No. 2013/047758.

Reference example 1
Light yellow crystals using 15.0 g of 5-hydroxy-1H-imidazol-4-carboxamide hydrochloride dihydrate in the same manner as in Example 12 (1) of WO 2013/047758. As a result, 13.9 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloride dihydrate was obtained.

Synthesis example 1
Under a nitrogen atmosphere, 10.0 g of 5-hydroxy-1H-imidazol-4-carboxamide hydrochloride dihydrate produced according to the method described in Reference Example 1 was added to 120 mL of 0.45 mol / L hydrochloric acid, and the mixture was heated to 47 ° C. Was dissolved. To the obtained solution, 10 mL of a 1.5 mol / L monosodium dihydrogen phosphate aqueous solution was added dropwise at 46 to 47 ° C. To the obtained solution, 50 mg of 5-hydroxy-1H-imidazol-4-carboxamide 3/4 hydrate was added as a seed crystal, and the mixture was stirred at 46 to 48 ° C. for 30 minutes. After confirming the precipitation of crystals of the reaction mixture, 60 mL of a 1.5 mol / L monosodium dihydrogen phosphate aqueous solution was added dropwise to this solution at 47 to 48 ° C. The reaction mixture was cooled to 0 ° C., stirred for 1 hour, and the precipitated crystals were collected by filtration.
The obtained crystal was divided into two, and one of the crystals was air-dried to obtain 3.23 g of an unwashed product of 5-hydroxy-1H-imidazol-4-carboxamide 3/4 hydrate as a white crystal. ..

The other crystal was washed successively with a mixture of 5.0 mL of acetone and 10.0 mL of water and 15.0 mL of acetone, and then air-dried to obtain 5-hydroxy-1H-imidazol-4-carboxamide-3 as white crystals. 2.94 g of a washed product of / 4hydrate was obtained. Each IR matched.
Moisture content: Unwashed product: 9.8%, Washed product: 8.8%
IR (cm ^-1 ): 3437, 1618, 1587, 1436
In Example 1 below, 3/4 hydrate of Compound A produced according to the method described in Synthesis Example 1 was used.

Example 1: Acquisition of azacitidine resistance of leukemia cell line and preventive effect by 3/4 hydrate of compound A (hereinafter, 3/4 hydrate of compound A is also simply referred to as compound A) SKM- as a leukemia cell line 1 (Pharmaceutical Infrastructure, Health and Nutrition Research Institute) was used. Cell culture was performed in RPMI 1640 medium (Life technologies) containing 1% penicillin / streptomycin and 10% fetal bovine serum (FBS) in _{an environment of 37 ° C., 5% CO 2} , and water vapor saturation.

In order to investigate the preventive and inhibitory effects of compound A on the acquisition of azacitidine resistance, a culture solution without additive (control group), a culture solution containing only azacitidine (Aza group), and a culture solution containing 1 μmol / L of compound A and azacitidine. Four groups of (Aza + A1 group) and a culture solution containing 10 μmol / L compound A and azacitidine (Aza + A10 group) were prepared and each was subjected to long-term culture. The azacitidine concentration started at 50 nmol / L and was doubled at 2-4 week intervals. When the concentration of azacitidine reached 1.6 μmol / L and the cells were cultured for 2 weeks, a cell proliferation test for azacitidine in each treatment group was carried out.

In the cell proliferation test, cells were first suspended in a medium and adjusted to 111111 cells / mL, and 90 μL (10000 cells) were seeded per well on a 96-well plate (Corning). Next, 10 μL of PBS solution of azacitidine (0, 3, 10, 30, 100 or 300 μmol / L) was added to the plate, and the cells _{were cultured in an environment of 37 ° C., 5% CO 2} , and water vapor saturation for 72 hours.

Then, the relative value of the number of cells of each cancer cell after the above culture was measured by a plate reader (Envision, PerkinElmer) as the luminescence intensity using a CellTiter Glo (Promega) reagent. The number of cells having an azacitidine concentration of 0 μmol / L was set to 100%, the luminescence intensity of the sample containing no cells was set to 0%, and the relative value of the luminescence intensity at each azacitidine concentration was calculated as a relative value. The results of each group were plotted with the azacitidine concentration (μmol / L) on the horizontal axis and the emission intensity (relative value) on the vertical axis.

These results are shown in FIG. FIG. 1 is a graph showing the luminescence intensity (relative value) of each of the above cancer cells. The terms in the figure mean the following.
Control: Untreated SKM-1 cells.
Aza: SKM-1 cells treated for 4 months while gradually increasing the treatment concentration of azacitidine (50 nmol / L to 1.6 μmol / L).
Aza + A1: SKM-1 cells to which 1 μmol / L of compound A was added throughout the treatment period in addition to the treatment of the Aza group.
Aza + A10: SKM-1 cells to which 1 μmol / L of Compound A was added throughout the treatment period in addition to the treatment of the Aza group.

As shown in FIG. 1, in all cancer cells, the luminescence intensity (relative value), which is considered to be an index of the number of cells, is attenuated depending on the concentration of azacitidine, and the number of living cells is decreasing. Shown. However, in the Aza group, the dose-response curve moved to the right side (high concentration side of azacitidine) as compared with the control group, indicating that the sensitivity to azacitidine was decreased, that is, resistance was acquired. On the other hand, the dose-response curves of the Aza + A1 group and the Aza + A10 group were almost the same as those of the control group, and it was found that the sensitivity to azacitidine was maintained. From these results, it was found that Compound A has a preventive effect or an inhibitory effect on the acquisition of azacitidine resistance. When administered to patients, the trough value (minimum blood drug concentration in the steady state) of compound A at 50 to 500 mg / m ² and repeated oral administration twice daily is about 1 to 10 μmol / L.

Pharmaceutical example 1
The active ingredient 5-hydroxy-1H-imidazol-4-carboxamide 3/4 hydrate 276.59 g, lactose hydrate (Pharmatose 200M, manufactured by DMV-Fontera Expiients) 39.46 g, carmellose calcium (ECG-). 505, 32.01 g (manufactured by Nichirin Chemical Industry Co., Ltd.) and 20.01 g of crystalline cellulose (KG-1000, manufactured by Asahi Kasei Co., Ltd.) were added to obtain a mixture. 12.00 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) is dissolved in 456.00 g of water, and 12.00 g of light anhydrous silicic acid (Aerosil-200, manufactured by Nippon Aerosil Co., Ltd.) is further dispersed. An aqueous solution was prepared. The prepared aqueous solution was sprayed on the obtained mixture, granulated with a fluidized bed granulator (FD-MP-01, manufactured by Paulec Co., Ltd.), and then dried to obtain granulated powder. To 360.38 g of the obtained granulated powder, 7.35 g of magnesium stearate (manufactured by Merck & Co., Inc.) sieved through a sieve with an opening of 180 μm was added, and a V-type mixer (mixer S-5 type, Tsutsui Rikagaku Kikai Co., Ltd.) was added. ) Was mixed at 30 rpm for 60 minutes to obtain a mixed powder. The obtained mixed powder was tableted with a rotary type tableting machine (PICCOLA B-10, manufactured by RIVA) using a double radius (12R × 3Rmm) surface punch having a tablet diameter of 8.5 mm at a tableting pressure of 10 kN. A round uncoated tablet of 320 mg was obtained per tablet. The amount of the active ingredient of the uncoated tablet was 200 mg. The tablet hardness of the uncoated tablet was 76 N as a result of measurement using a tablet hardness meter 8M (manufactured by Schleunigel).

A coating agent (Opadry 03A470001 TAN (hypromellose 2910: 60.00%, talc: 20.00%, titanium oxide: 18.86%, yellow iron sesquioxide: 1. 00%, black iron oxide: 0.14%), manufactured by Nippon Colorcon Co., Ltd.) was coated with a coating machine (DRC-200, manufactured by Paulec Co., Ltd.) to obtain a circular film-coated tablet. Further, in the same manner, tablets having an active ingredient amount of 50 mg and 100 mg were produced and used in the following examples.

Example 2: Administration to MDS patients MDS patients (18 years or older) were administered compound A at ^{a single dose of 400 mg / m 2} twice daily for 14 days, and azacitidine was administered on the same day as the start date of administration of compound A. Start administration of. Azacitidine is administered subcutaneously or intravenously at a dose of 75 mg / m ^{2 for 7 days.} One treatment cycle is 28 days. After administration for 7 days, the drug is withdrawn for 21 days. From this example, the preventive or inhibitory effect of the pyrimidine antimetabolite on resistance can be confirmed.

Example 3: Administration to MDS Patients MDS patients (18 years and older) were administered Compound A at ^{a single dose of 400 mg / m 2} twice daily for 21 days and azacitidine at a dose of ^{75 mg / m 2.} Administer subcutaneously or intravenously for 7 days. One treatment cycle is 28 days. After administration for 7 days, the drug is withdrawn for 21 days. From this example, the preventive or inhibitory effect of the pyrimidine antimetabolite on resistance can be confirmed.

Example 4: Administration to MDS patients MDS patients (18 years or older) were administered compound A at ^{a single dose of 300 mg / m 2} twice daily for 14 days, and azacitidine was administered on the same day as the start date of administration of compound A. Start administration of. Azacitidine is administered subcutaneously or intravenously at a dose of 75 mg / m ^{2 for 7 days.} One treatment cycle is 28 days. After administration for 7 days, the drug is withdrawn for 21 days. From this example, the preventive or inhibitory effect of the pyrimidine antimetabolite on resistance can be confirmed. In the case of Example 4, side effects in the patient can be reduced. The administration start date of Compound A may be earlier than the administration start date of azacitidine. Further, as in Example 3, it can be administered twice a day for 21 days.

Example 5: Administration to MDS patients MDS patients (18 years or older) were administered compound A at ^{a single dose of 200 mg / m 2} twice daily for 14 days, and azacitidine was administered on the same day as the start date of administration of compound A. Start administration of. Azacitidine is administered subcutaneously or intravenously at a dose of 75 mg / m ^{2 for 7 days.} One treatment cycle is 28 days. After administration for 7 days, the drug is withdrawn for 21 days. From this example, the preventive or inhibitory effect of the pyrimidine antimetabolite on resistance can be confirmed. In the case of Example 4, side effects in the patient can be reduced. The administration start date of Compound A may be earlier than the administration start date of azacitidine. Further, as in Example 3, it can be administered twice a day for 21 days.

Patients with MDS in Examples 2 to 5 showed the therapeutic effect with the following items: Results of azacitidine monotherapy + BSC (Best Supportive Care: supportive care. Administration of blood transfusion, antibiotics, analgesics, antipyretic agents, antiemetics, etc. as needed) (Foreign phase III study "AZA-001") will be compared and evaluated. The period during which the resistance of the pyrimidine antimetabolite in the above patients can be prevented or suppressed is preferably 3 months or longer, preferably 4 months or longer, preferably 5 months or longer, preferably 6 months or longer. It is preferably one year or more.

<Evaluation of therapeutic effect 1>
Time to live (median). The outcome of azacitidine in the AZA-001 study is 24.5 months, which is expected to exceed that in the present invention. The survival time is preferably 25 months or longer, preferably 26 months or longer, and preferably 28 months or longer.

<Evaluation of therapeutic effect 2>
2-year survival rate. The result of azacitidine in the AZA-001 study was 50.8%. It is assumed that this is exceeded in the present invention. The 2-year survival rate is preferably 51% or more, preferably 53% or more, and preferably 55% or more.

<Evaluation of therapeutic effect 3>
Median time to AML transition or death.
The outcome of azacitidine in the AZA-001 study is 13.0 months, which is expected to exceed that in the present invention. The median time to AML transition or death is preferably 14.0 months or longer, preferably 15.0 months or longer, preferably 17.0 months or longer, and 20.0 months or longer. Is preferable.

<Evaluation of therapeutic effect 4>
Median time to AML transition.
The outcome of azacitidine in the AZA-001 study is 20.7 months, which is expected to exceed that in the present invention. The median time to AML transition is preferably 21.0 months or longer, preferably 22.0 months or longer, preferably 24.0 months or longer, and 27.0 months or longer. Is preferable.

<Evaluation of therapeutic effect 5>
Survival rate.
In the present invention, it is assumed that the results of azacitidine (Kaplan-Meier curve of survival time) in the AZA-001 study are exceeded. The survival rate after one year is preferably over 70%, preferably over 71%, preferably over 72%, preferably over 75%, and preferably over 80%.

<Evaluation of therapeutic effect 6>
Hematological remission rate according to the IWG criteria (2000 edition).
The results of azacitidine in the AZA-001 study and the hematological remission rate were 6.7%, but it is assumed that this is exceeded in the present invention. The hematological remission rate is preferably 7% or more, preferably 8% or more, and preferably 9% or more.

<Evaluation of therapeutic effect 7>
Hematological improvement rate according to the IWG criteria (2000 version).
The results of azacitidine in the AZA-001 test and the hematological improvement rate were 49.2%, but it is assumed that this is exceeded in the present invention.
The hematological improvement rate is preferably 50% or more, preferably 52% or more, and preferably 54% or more.

<Evaluation of therapeutic effect 8>
The need for red blood cell transfusion.
Azacitidine results in the AZA-001 study, the percentage of patients who became independent of red blood cell transfusion dependence, ie, did not receive red blood cell transfusion for 56 consecutive days or more during the study period, 45.0%. It is assumed that this is exceeded in the present invention.
The proportion of patients who became independent from red blood cell transfusion dependence is preferably 48% or more, preferably 50% or more, preferably 55% or more, and preferably 60% or more.

<Evaluation of therapeutic effect 9>
The need for platelet transfusions.
Azacitidine results in the AZA-001 study, the percentage of patients who became independent of platelet transfusion dependence, ie, did not receive platelet transfusions for 56 consecutive days or more during the study period, 42.1%. It is assumed that this is exceeded in the present invention.
The proportion of patients who have become independent from platelet transfusion dependence is preferably 45% or more, preferably 50% or more, preferably 55% or more, and preferably 60% or more.

The present invention is useful as a therapeutic agent for cancers such as blood cancer.

Claims (17)

Pyrimidine antimetabolite and
A combination drug comprising 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof.
A single dose of 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is 50 to 500 mg / m ² , and a daily dose is 100 to 1000 mg / m ² .
Combination medicine. The combination drug according to claim 1, wherein resistance to a pyrimidine antimetabolite is prevented or suppressed. The combination drug according to claim 1 or 2, wherein the administered patient has at least one improvement of:
(A) The median time to AML transition or death is 14.0 months or greater.
(B) The median time to AML transition is 21.0 months or longer.
(C) The proportion of patients who became independent from red blood cell transfusion dependence is 48% or more.
(D) The proportion of patients who became independent from platelet transfusion dependence is 45% or more. The combination drug according to claim 2, wherein the period during which resistance to the pyrimidine antimetabolite can be prevented or suppressed is 3 months or longer. The combination drug according to any one of claims 1 to 4, wherein the pyrimidine antimetabolite is a compound selected from the group of azacitidine, decitabine, cytarabine and gemcitabine or a salt thereof or a hydrate thereof. The combination drug according to any one of claims 1 to 5, wherein the single dose of 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is 370 to 430 mg / m ^2. The pyrimidine antimetabolite is azacitidine or a salt thereof or a hydrate thereof.
The combination drug according to any one of claims 1 to 6, wherein the daily dose of azacitidine or a salt thereof or a hydrate thereof is 70 to 80 mg / m ^2. The combination drug according to any one of claims 1 to 7, wherein the pyrimidine antimetabolite is azacitidine or a salt thereof or a hydrate thereof, and azacitidine or a salt thereof or a hydrate thereof is administered for 7 days. The pyrimidine antimetabolite is azacitidine or a salt thereof or a hydrate thereof, and azacitidine or a salt thereof or a hydrate thereof is administered in a plurality of cycles with a 7-day administration period and a subsequent drug holiday as one cycle. The combination drug according to any one of claims 1 to 8 to be administered. The combination drug according to any one of claims 1 to 9, wherein 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is administered for 14 to 28 days. 10. The combination drug described. From claim 1, a pyrimidine antimetabolite is subcutaneously or intravenously administered by infusion, and 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is intravenously orally administered by infusion. The combination drug according to any one of 11. The combination drug according to any one of claims 1 to 12, for the treatment of blood cancer. The combination drug according to any one of claims 1 to 13, for the treatment of myelodysplastic syndrome or acute myeloid leukemia. Any one of claims 1 to 14, wherein the pyrimidine antimetabolite and 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof are provided as the same or separate pharmaceutical compositions. The combination drug described in the section. A prophylactic or inhibitory agent for the resistance of a pyrimidine antimetabolite, which comprises 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof. A method of treating a disease, which comprises administering azacitidine or a salt thereof or a hydrate thereof and 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof.
The daily dose of azacitidine or a salt thereof or a hydrate thereof is 70 to 80 mg / m ² .
A single dose of 5-hydroxy-1H-imidazol-4-carboxamide or a salt thereof or a hydrate thereof is 50 to 500 mg / m ² , and a daily dose is 100 to 1000 mg / m ² .
Method.

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